The present invention relates to erythropoietin and the use thereof in the treatment of cancer.
BTRxe2x80x94blood transfusion requirements; Epoxe2x80x94erythropoietin; Hbxe2x80x94hemoglobin; MMxe2x80x94multiple myeloma; PSxe2x80x94performance status; rHuEpoxe2x80x94recombinant human erythropoietin.
Human erythropoietin (Epo) is a 30.4 kD glycoprotein hormone primarily produced and secreted by the kidneys. Epo normally circulates in the bloodstream and serves as the main erythroid hormone, i.e. it is responsible for the regulation and control of red blood cell production through stimulation of the proliferation and differentiation, as well as maintaining survival, of the erythroid series (Spivak et al., 1991; Mittelman, 1993). Epo interacts with a specific receptor located on the bone marrow (BM) erythroid progenitors burst-forming unit-erythroid (BFU-E) and mainly colony-forming unit-erythroid (CFU-E).
Israel Patents IL 73785, 96581, 96582 and 100935 and corresponding U.S. Pat. Nos. 5,441,868, 5,547,933, 5,618,698 and 5,621,080 describe for the first time the DNA sequence encoding human Epo and the purified and isolated polypeptide having part or all of the primary structural conformation and the biological properties of naturally occurring Epo. An isolated Epo glycoprotein is disclosed that has the in viva biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells and is useful for treatment of blood disorders, such as anemia. International PCT publication WO 91/05867 describes Epo isoforms obtained by expression of exogenous DNA in eukaryotic host cell and said to be useful for increasing hematocrit levels in mammals by increasing production of reticulocytes and red blood cells.
European Patent Application EP 358463 discloses a method for purification of Epo intended for use in the treatment of anemia, including that found in patients on renal dialysis for kidney failure, anemia associated with cancer, aplastic anemia, anemia due to blood loss and anemia associated with chronic renal disease, and to increase red blood cell mass prior to blood donation. U.S. Pat. No. 4,745,099 describes compositions comprising Epo for treating anemia caused by malignant tumors. Japanese Patent No. 2632014 describes therapeutic agents containing human Epo as active substance for treatment of anemia caused by bone marrow dysfunction, or due to radiation exposure or administration of carcinostatic substance.
Cloning of the Epo gene (Lin et al., 1985) and introduction of recombinant human Epo (rHuEpo) into clinical practice gave hope to many patients suffering from anemia. The first to benefit from rHuEpo therapy were patients with end stage renal failure, since they lack endogenous Epo production because of the non functioning kidneys (Eschbach et al., 1989). The high success rate with these patients led to a large series of clinical trials, achieving varying results in increasing hemoglobin (Hb) and ameliorating anemia associated with AIDS (Henry et al., 1992), chronic diseases (Schreiber et al., 1996), and various malignancies such as solid tumors, myelodysplastic syndromes and multiple myeloma (Ludwig et al., 1990, 1993a and 1993b; Spivak, 1994; Mittelman et al., 1992 and 1997; Cazzola et al., 1995).
In all the above-mentioned patent documents and medical literature Epo is indicated only for the treatment of anemia. Two recent articles described treatment of renal cell carcinoma with Epo: Rubins (1995) described transient tumor regression in a single patient with renal cell cancer who had been treated with Epo for anemia, and Morere et al. (1997) reported a study of 20 patients with metastatic renal cell carcinoma who received rHuEpo: one patient achieved xe2x80x9ccomplete anti-tumor responsexe2x80x9d, another patient demonstrated partial response and 2 minor responses were further observed. These isolated observations with renal cell cancer patients do not indicate nor suggest a broad use of Epo in other malignancies.
It has now been surprisingly found according to the present invention that erythropoietin triggers immune responses that affect tumor regression and thus can be used in the treatment of cancer.
The present invention thus relates to pharmaceutical compositions for the treatment of cancer, excepting renal cell cancer, comprising erythropoietin and a pharmaceutically acceptable carrier. These compositions are useful for inhibition of tumor growth, triggering of tumor regression, stimulation of the natural immunological defense against cancer and/or inhibition of cancer cell metastasis.
The compositions of the invention can be used for treatment of solid tumors such as, but not being limited to, bladder, breast, cervix, colon, esophagus, larynx, liver, lung, ovary, pancreas, prostate, stomach, thyroid, uterus, vagina and vocal cord cancer, as well as of non-solid malignant neoplasms such as, but not being limited to, neoplasms of the blood-forming tissues such as leukemias, for example chronic lymphocytic leukemia (CLL), neoplasms of the reticuloendothelial and lymphatic systems such as lymphomas, and plasma cell dyscrasias such as multiple myeloma.
Any form of biologically active erythropoietin may be used according to the invention. These forms of biologically active erythropoietin include, but are not limited to, recombinant erythropoietin and analogs as described in U.S. Pat. Nos. 5,441,868, 5,547,933, 5,618,698 and 5,621,080 as well as human erythropoietin analogs with increased glycosylation and/or changes in the amino acid sequence as those described in European Patent Publication No. EP 668351 and the hyperglycosylated analogs having 1-14 sialic acid groups and changes in the amino acid sequence described in PCT Publication No. WO 91/05867. In a most preferred embodiment, the erythropoietin is recombinant human erythropoietin.
The invention relates also to the use of erythropoietin for the preparation of a medicament for the treatment of cancer, excepting renal cell cancer.
In a further aspect, the invention provides a method for treatment of cancer, excepting renal cell cancer, which comprises administering to a cancer patient an amount of erythropoietin effective for inhibition of tumor growth, triggering of tumor regression, stimulation of the natural immunological defense against cancer and/or inhibition of cancer cell metastasis in said patient.